It has been demonstrated that the T cell proliferative response to Con A and the T cell dependent antibody responses to the soluble antigens TNP-KLH, TNP-T,G-(A-L), and TNP-Nuclease require the participation of adherent, radio-resistant, non-T, non-B and accessory cells which express Ia (I region associated) determinants. In addition, I-A and I-E positive cells within the splenic adherent cell population are the predominant stimulators of the one way murine mixed lymphocyte response when responder and stimulator cells differ either at H-2 or the M1s locus. Studies designed to analyze the functional importance of specific determinants on Ia molecules were carried out employing a battery of monoclonal anti-I-E reagents specific for different epitopes on the same I-E product molecules. Inhibition studies demonstrated that different clones of antigen-specific and I-E restricted T cells recognize antigen in association with different epitopes on a given I-E molecule.